CN107530290A - Slow release medical composition containing rivastigmine - Google Patents
Slow release medical composition containing rivastigmine Download PDFInfo
- Publication number
- CN107530290A CN107530290A CN201680024737.4A CN201680024737A CN107530290A CN 107530290 A CN107530290 A CN 107530290A CN 201680024737 A CN201680024737 A CN 201680024737A CN 107530290 A CN107530290 A CN 107530290A
- Authority
- CN
- China
- Prior art keywords
- rivastigmine
- sustained release
- medical composition
- release
- slow release
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 title claims abstract description 101
- 229960004136 rivastigmine Drugs 0.000 title claims abstract description 96
- 239000000203 mixture Substances 0.000 title claims abstract description 38
- 238000013268 sustained release Methods 0.000 claims abstract description 102
- 239000012730 sustained-release form Substances 0.000 claims abstract description 100
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- 229920002521 macromolecule Polymers 0.000 claims description 8
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- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The present invention relates to the slow release medical composition containing rivastigmine, more specifically, the present invention relates to a kind of slow-releasing preparation containing pH dependence sustained release phases, it is related to a kind of by controlling the release for making to take in rear stomach and intestine at initial stage to reach minimum, so as to while effective blood drug concentration is reached, highest blood concentration (cm) can also be reduced compared to existing product to reduce side effect, the slow release medical composition of the rivastigmine of effective blood drug concentration can be maintained by the sustained release of principal component afterwards.As a result, only being taken within one day according to the medical composition of the present invention once can just reach the usage identical effect for taking 2 times with existing one day, and by improving the medication convenience of patient, so as to the effect with the therapeutic efficiency that can improve patient.
Description
Technical field
The present invention relates to the slow release containing rivastigmine (SUSTAINED-RELEASE) medical composition, it is more specific and
Speech, the present invention relates to one kind to contain pH- dependence sustained releases phase (pH-dependent delayed release phase)
Slow-releasing preparation, be related to after taking while by intestines and stomach one side sustained release principal component to maintain effective blood drug concentration, from
And only take within 1st the delaying containing rivastigmine that once can just reach the usage identical effect for taking 2 times with existing one day
Release sex medicine composition.
Background technology
Generally, medicine rivastigmine (Rivastigmine) is as slightly to the alzheimer's sea Mo Shi types of moderate
And Parkinson dementia treatment agent, it is administered 2 times within 1st with 1.5mg~6mg dosage.The known medicine mainly passes through esterase (example：
Acetylcholinesterase and butyrylcholine esterase) it is metabolized, and there is the blood halflife of 1 hour, due to blood halflife such as
This short, therefore had difficulties in terms of the exploitation once a day sustained release agent of usage.In addition, the currently marketed medicine, because fast
Quick-release is put so as to have high highest blood concentration (C in the early stagemax), therefore also asking with high-frequency gastrointestinal side effect
Topic.
Therefore, all the time in order to solve this problem of medicine, generally to using polymer matrix (polymer
Matrix) sustained release of system is studied.But polymer matrix system is difficult control to be had as rivastigmine
The burst size at initial stage of the medicine of high water solubility, in addition, it is relative low in latter half release amount of medicine, therefore be not suitable for persistently releasing
Put uniform amount.In addition, although korean patent application the 2012-7003314th discloses while has quick-acting and continuation
Sustained release agent, but still the side effect that initial stage, high blood concentration was brought be present, can not actually realize long-term sustained release with
Meet once a day usage.
Although disclosed in Korean Patent No. 603900 or Korean Patent No. 661441 containing rivastigmine when
The sustained release agent of m- control mode, but utilize semipermeability film when m- control mode sustained release agent, the medicine being time controlled
Thing can discharge in a flash after some period of time, therefore can still have side effect at corresponding time point.Therefore, at present
Untill do not develop the rivastigmine preparation of once a day usage also, there is an urgent need to it is further developed.
The content of the invention
Problems to be solved by the invention
Therefore, the technical problem to be solved in the present invention is the hydrophily for having high water solubility on such as rivastigmine etc.
The sustained release of medicine, it is after the obtained pH- dependence sustained release phases, it in the form of with sustained release mutually one or is separated
Form is included in preparation, so that the insoluble drug release after drug administration in initial stage stomach and intestine reaches minimum, and is being passed through
The release and absorption of small intestine and large intestine and long-term equably maintenance active ingredient.Thus, control releasing in stomach and intestine at initial stage is passed through
Put, to reduce highest blood concentration (Cmax), so that side effects of pharmaceutical drugs reach minimum, maintained afterwards by sustained release
Effective blood drug concentration, and then the rivastigmine slow release medical composition of once a day usage is provided.
The means used to solve the problem
The present invention relates to one to take once and containing the slow release containing rivastigmine of pH- dependence sustained release phases
Medical composition.
Macromolecule of the pH- dependences sustained release mutually containing the property with dissolving in more than pH5.0, and institute
State the slow release medical composition containing rivastigmine and be prepared to particle, ball, core tablet (core tablet) form.
The macromolecule of the property with dissolving can be selected from acrylic copolymer, hydroxypropyl only in more than pH5.0
One or more of ylmethyl cellulose phthalate, cellulose acetate phthalate and their mixture.
The rivastigmine that the pH- dependences sustained release mutually contains accounts for 25~90 weights of total rivastigmine content
Measure % scopes.
On the basis of the pH- dependences sustained release phase, it can further contain pH- dependent/non-dependent sustained-release matrixes.
The medical composition can contain pH- dependent/non-dependents sustained release phase, and pH- dependent/non-dependents sustained release is mutually in and pH-
The form of dependence sustained release phase one or the form of separation.
The pH- dependent/non-dependents sustained release can be mutually matrix, particle, the form of ball.
The rivastigmine that the pH- dependent/non-dependents sustained release mutually contains accounts for 10~75 weight % of total rivastigmine content
Scope.
The rivastigmine of the medical composition dissolution is total rivastigmine content within 120 minutes initial stages of dissolution
10 weight % are that 40 weight % are less than 70 weight %, in 12 hours less than 40 weight %, in 6 hours
More than 70 weight %.
Hereinafter, the present invention is described in detail.
The present invention relates to the rivastigmine slow release medical composition containing pH- dependence sustained release phases, Ke Yitong
Cross in the following manner realization.There is the macromolecule of dissolving characteristic, system using pH- dependent polymers, during specifically used more than pH5.0
The standby sustained release phase being made up of the particle or bead (pellet) coated, obtained sustained release is set mutually to be contained in sustained release phase base
Inside matter, or a tablet or hard capsules formulation are prepared into together with sustained release phase particle or bead.
The drug effect performance of the medical composition of the present invention is as follows：Initial stage, the rivastigmine included in sustained release phase are slow
Release, so as to reach the effective blood drug concentration of minimum；Afterwards, in the small intestine and large intestine that pH is more than 5.0, with sustained release phase
Together, the rivastigmine of pH- dependence sustained release phases slowly discharges rivastigmine, so as to be maintained in whole intestines and stomach
Uniformly release.
Here, the pH- dependences sustained release of the present invention mutually can use pH- dependent polymers, specifically, can make
It is standby into using macromolecule during more than pH5.0 with dissolving characteristic come the particle or bead that coat.Specifically, by inert core
Rivastigmine coating liquid is sprayed on (Inert core) come after forming the coat as principal component, then spray containing pH- according to
Rely the coating liquid of property polymer, so as to form sustained release coat, it is possible thereby to postpone the release of medicine.
Inert core is preferably a diameter of 100- being made up of microcrystalline cellulose, lactose, white sugar, dextrin and their mixture
300 μm have an evenly sized spherical particle.In terms of total particle or small ball weight, inert core can account for 10~60% weight
Than.After principal component coat can be by the way that rivastigmine be dissolved into appropriate solvent together with adhesive, it is sprayed onto lazy
On property core and it is made.Hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose can be used as suitable adhesive
Element, polyvinylpyrrolidone, polyvinyl alcohol, Utech (Eudragit) and their mixture, and to be used in coat
Rivastigmine meter, adhesive can be used with 0.1~20.0% weight ratio.It can be used as suitable solvent
Water, ethanol, isopropanol, acetone, dichloromethane and their mixed solvent.In order that process is smoothly implemented, can further make
With suitable plasticizer and lubricant, as suitable plasticizer polyethylene glycol, triethyl citrate, three acetic acid can be used sweet
Grease, DAS di alkyl sebacate, diethyl phthalate etc., talcum powder, glycerol monostearate can be used as lubricant
Ester, colloidal silicon dioxide etc., but it is not limited to this.
The method that another kind forms the particle containing principal component is as follows.Containing principal component and suitable pharmacy excipient
Mixture in add slurry, so as to which combination be made, and make sieve nest of the combination by extruder (extruder)
(sieve), so as to which columnar particulate matter be made, afterwards, spheric granules is finally made using marble forming machine (spheronizer).
PH- dependences, which are added, in the spherical principal component particle prepared by sprinkling or extrusion way postpones coat,
So as to realize the pH- dependence sustained release phases of the present invention, pH- dependences delay coat, which can use to have, only to exist
The coating substance of the characteristic dissolved during more than pH5.0, you can to use acrylic copolymer, hydroxypropyl methyl cellulose neighbour's benzene
Dicarboxylic acid esters, cellulose acetate phthalate and their mixture.Especially as acrylic copolymer, can use
Eudragit L100-55, Utech L100, Utech S100 and their mixture or aqueous dispersion solution, but it is not limited to this.
These macromolecules can be dissolved into solvent together with suitable plasticizer and lubricant or be used in the form of scattered, can also be made
This while comprising plasticizer and lubricant the commercialized product with refined gram suitable (Acryl-Eze).To contain principal component or principal component
The particulate matter weight meter of coat, the weight ratio that the usage amount that pH- dependences postpone coat is 10~100%, preferably with 30
~60% weight ratio uses.When usage amount is less than 10%, it is difficult to control discharge the initial stage of principal component, when usage amount exceedes
When 100%, because elongated for dissolving time needed for pH- dependence coats, so as to which carryover effects can be caused.
In order to which regulating drug is from the release of particulate matter, slow release characteristic can be added in pH- dependence sustained release phases.Can
When preparing the principal component particulate matter of principal component coat and extrusion way, to make it include the macromolecule of high viscosity to be made
It is standby, regulatory function is realized with this, can also be come on the spheric granules thing prepared using pH- dependent/non-dependents sustained-release matrixes
It is coated, regulatory function is realized with this.Ethyl cellulose, methylcellulose, acrylic copolymer, hydroxypropyl can be used
Methylcellulose etc., preferably using insoluble polymers such as ethyl celluloses, commercially available ethyl cellulose water can also be used
Dispersion liquid (Surelease) product.In terms of principal component particulate matter, sustained-release matrix can be used with 3~60% weight ratio.Institute
State sustained-release matrix and play booster action, i.e. by reducing the usage amount of pH- dependence sustained release phases, to shorten needed for process
Time, but also by control pH- dependences coat dissolve after medicine abrupt release, to allow medicament to uniformly discharge.
This pH- dependences sustained release phase, suppress the release in stomach and intestine, initial stage can be made a large amount of because of rivastigmine
The caused side effect of release reaches minimum, and the prolonged demurrage under the alkaline environment such as small intestine and large intestine afterwards
Between, slowly release, so as to the function with the release time for further extending medicine.But the release amount of medicine in stomach and intestine
When excessively being adjusted, the patient that the time for reaching effective blood drug concentration is elongated, especially relatively long to the gastrointestinal retention time can be made
For, be not suitable for.As the method for making up the problem, the present invention further contain independent sustained release phase, sustained release be mutually pH- it is non-according to
Lai Xing, it can be included in the form of matrix or other particles, ball etc..
In the present invention as realize simultaneously containing pH- dependence sustained release phases and release phase method, can use with
Lower method.By the way that the particle or ball that are prepared into pH- dependence sustained release phases are mixed into the rivastigmine containing ormal weight
Sustained-release matrix in, so as to prepare piece agent (tablet) form, or after preparing the sustained release phase of particle or pellet in addition, one
Compression piece agent (tablet) is played, or is added in hard capsules (capsule) and is prepared into capsule formulation.
Sustained-release matrix can be by making using hydrophily and the mesh (network) of water-insoluble sustained-release matrix equably
Rivastigmine comprising ormal weight and pH- dependences sustained release are mutually made, and as sustained-release matrix, use hydroxypropyl methyl
Cellulose, ethyl cellulose, hydroxyethyl cellulose, carbomer, polyvinylpyrrolidone-vinyl acetate co-polymer and they
Mixture, can be by adding conventional pharmacy excipient, so as to prepare for the mixture of ingot processed or by wet type
The particulate matter made from process such as grain or dry type particle, is compressed, so as to prepare piece agent afterwards.The sustained release of these sustained-release matrixes
Mutually it is formed into, its release amount of medicine maintains uniformly can be according to usage amount without being had differences the change because of pH, and also
Only the rate of release of medicine is adjusted, therefore can also start release medicine in the stomach and intestine with relatively low pH.
, can be with addition, sustained release can mutually be prepared as the particle and ball of form independently of pH dependence sustained release phases
Using conventional extended release matrix and pharmacy excipient, and pass through wet granulate, dry type particle, fluid bed granulate and fluidized bed coating process
It is prepared by method.The sustained release phase of independent form, it can be put into together with pH- dependences sustained release phase in hard capsules,
So as to be prepared into capsule formulation；Or can also further admixed excipients, diluent, lubricant, stabilizer or adhesive etc.
Conventional additive is prepared into conventional tablet, multilayer tablet and dry coated tablet (dry coated tablet) form.
Preferably, the rivastigmine content of sustained release phase of the invention includes total principal component (rivastigmine content) content
In 10~75 weight % scopes, specifically, further preferred 10~50 weight %, most preferably 15~35 weight %.Due to
These principal components are slowly discharged from sustained release phase, rather than rapid release, therefore initial stage, burst size was controlled in ormal weight, with showing
Some conventional tablets are compared, and can reduce highest blood concentration (Cmax), so as to reduce gastrointestinal side effect.
Finally, for the medical composition of the present invention, within 120 minutes initial stages of dissolution, 10 weights of dissolution total content
% is measured less than 40 weight %, the weight % of dissolution 40 is less than 70 weight % in 6 hours, the weight of dissolution 70 in 12 hours
Measure more than %.To find out its cause, for the situation of release with regard to carrying out principal component in stomach, if molten within 120 minutes initial stages of dissolution
Output exceedes 40 weight % of total content, then still occurs the problems of in the prior art, i.e. the excessive of principal component is released
Put caused gastrointestinal side effect；If burst size is less than 10 weight %, it is difficult to reach initial effective blood drug concentration, so as to
Drug effect display delay.In addition, also make the medical composition of the present invention, the rivastigmine that sustained release is uniformly measured afterwards, with
Effective blood drug concentration is persistently maintained, so more than the 70% of total content should be discharged at 12 hours.Otherwise the medicine of administration can be made
Utilization rate in vivo reduces, it is therefore necessary to meets this standard.
Invention effect
The present invention relates to the slow release medical composition containing rivastigmine, the pH of medical composition of the invention in the early stage
In low stomach and intestine, the insoluble drug release of pH- dependence sustained release phases is reached minimum, and sustained release is mutually delayed Slow release,
So as to control discharge the initial stage of the hydrophilic medicaments such as the rivastigmine with water-soluble, therefore can not only reduce existing
Gastrointestinal side effect caused by high highest blood concentration (Cmax) caused by some ordinary preparations, additionally it is possible to reach effective blood medicine
Concentration.Afterwards, in small intestine and large intestine, although the amount for the rivastigmine that sustained release mutually discharges can gradually decrease, pH- is relied on
Property sustained release meet sustained release rivastigmine more than 12 hours, so can continue to maintain effective blood medicine of principal component dense
Degree.Once a day usage with water solubility and the very short medicine of blood halflife can be realized by the present invention, not only
Patient, which takes medicine, to be facilitated, and further improves drug compliance, additionally it is possible to while improve therapeutic effect.
Embodiment
Below, it is of the invention in order to help to understand, there is provided preferred embodiment and experimental example.But the following example and
Experimental example is merely to being more easily understood the present invention and providing, interest field of the invention is not limited to these embodiments and reality
Test example.
Embodiment 1
After 400g initiator core (cellet) 100 (180~250 μm) is fluidized in fluidized-bed coating machine, by 192g
Tartaric acid rivastigmine (Rivastigmine tartarate) and 20g hydroxypropyl methyl cellulose (Methocel
E5) and 138g talcum powder is added to ethanol and the in the mixed solvent of purified water (purified water) prepares coating liquid, and is sprayed with bottom
The mode of penetrating is sprayed, and medicine layer is formed so as to coat.Here, by spraying 1,080g aqueous ethylcellulose dispersion liquid
(Surelease) coating liquid in purified water is distributed to together with 100g talcum powder to increase slow release layer.In the spherical of formation
On particulate matter, prepared by refined gram of 560g suitable (Acryl-Eze) is distributed in purified water is sprayed with bottom spray regime
Coating liquid, so as to increase pH- dependence coats, described refined gram is Utech (Eudragit) preferably by pH- dependent polymers
L100-55 is formed.The particulate matter prepared according to the method described above, for standard weights 84mg, the tartaric acid rivastigmine containing 9.6mg
It is bright.
In addition, by 14.4g tartaric acid rivastigmine, 484.2g microcrystalline cellulose (microcrystalline cellulose 12
(Vivapur12)), 157.5g METHOCEL K100MCR (methylcellulose K100M (Methocel K100M)),
After 5.4g aluminium-magnesium silicate (Cab-O-Sil) and 10.5g magnesium stearate (Magnesium stearate) are mixed, in roller
Granulation is compressed in press (roller compactor), so as to prepare the dry type particulate matter of sustained release phase.
378.0g in obtained pH- dependences sustained release phase particulate matter (is contained into 43.2g tartaric acid rivastigmines
It is bright) and 672.0g (containing 14.4g tartaric acid rivastigmine) sustained release phase dry type particulate matter mixed after, rotary
It is compressed in tablet press machine (Rotary Tablet Press) so that tablet is made, and makes every sheet weight be 350mg.Contain in every
There is 19.2mg tartaric acid rivastigmine, and make to contain 14.4mg in pH- dependence sustained release phases, be sustained in phase and contain
4.8mg tartaric acid rivastigmine.
Embodiment 2-3
Embodiment 2 and embodiment 3 use same as Example 1 according to the raw material medicine component described in table 1 below
Method prepares the amount of 3,000.Embodiment 2 and embodiment 3 are that the total amount containing rivastigmine is 19.2mg in every, its
In, make the tartaric acid rivastigmine containing 9.6mg in the pH- dependence sustained release phases of embodiment 2, be sustained in phase and contain
9.6mg tartaric acid rivastigmine, make the tartaric acid profit containing 4.8mg in the pH- dependence sustained release phases of embodiment 3 all
This bright, the tartaric acid rivastigmine containing 14.4mg in sustained release phase
Table 1
Embodiment 4
After 400g initiator core 100 (180~250 μm) is fluidized in fluidized-bed coating machine, by 192g tartaric acid
Rivastigmine and 20g hydroxypropyl methyl cellulose (Methocel E5) and 108g talcum powder are added to ethanol and purification
The in the mixed solvent of water prepares coating liquid, and is sprayed with bottom spray regime, and medicine layer is formed so as to coat.Make what is formed
After spheric granules Logistics, spray 40g Opadry (Opadry) 03K19229 is dissolved into ethanol and purified water mixing it is molten
Coating liquid in agent, after increasing time coat, purification is preferably distributed to by refined gram of 780g to spray with bottom spray regime
Prepared by water coating liquid, so as to increase pH- dependence coats, refined gram is Utech preferably by pH- dependent polymers
L100-55 is formed.The particulate matter prepared according to the method described above, for standard weights 77mg, the tartaric acid rivastigmine containing 9.6mg
It is bright.
In addition, by 5.76g tartaric acid rivastigmine, 402.54g microcrystalline cellulose (microcrystalline cellulose 12
(Vivapur12)), 210.0g METHOCEL K100MCR (methylcellulose K100M (Methocel K100M)),
After 5.4g aluminium-magnesium silicate (Cab-O-Sil) and 10.5g magnesium stearate are mixed, granulation is compressed in roll squeezer,
So as to prepare the dry type particulate matter of sustained release phase.
415.8g in obtained pH- dependences sustained release phase particulate matter (is contained into 51.84g tartaric acid rivastigmines
It is bright) and 634.2g (containing 5.76g tartaric acid rivastigmine) sustained release phase dry type particulate matter mixed after, rotary
It is compressed in tablet press machine so that tablet is made, and makes every sheet weight be 350mg.Tartaric acid rivastigmine containing 19.2mg in every
It is bright, and make to contain 17.28mg in pH- dependence sustained release phases, be sustained the tartaric acid rivastigmine containing 1.92mg in phase
It is bright.
Embodiment 5
192g tartaric acid rivastigmine and 300g microcrystalline celluloses (Heweten101) and 268g lactose are hydrated
After thing (Pharmatose200) is mixed, add and 40g polyvinylpyrrolidone (PVP K-30) is dissolved into purified water
Slurry, so as to be made combination.Combination is set to pass through extruder (extruder) after obtained columnar particle, to utilize
Marble forming machine (spheronizer) prepares spherical principal component particulate matter.Principal component particulate matter is set to be fluidized in fluidized-bed coating machine
Afterwards, sprayed with bottom spray regime by 1,280g aqueous ethylcellulose dispersion liquid (Surelease) together with 80g talcum powder
Prepared by being distributed in purified water coating liquid, so as to increase sustained release coat.To the spherical sustained release particle thing of formation, utilize
Fluidized-bed coating machine sprays prepared by being preferably distributed to refined gram of 500g in purified water coating liquid with bottom spray regime, from
And increase pH- dependence coats, described refined gram is that Eudragit L100-55 is formed preferably by pH- dependent polymers.According to above-mentioned
Particulate matter prepared by method, for standard weights 85mg, the tartaric acid rivastigmine containing 9.6mg.
In addition, by 14.4g tartaric acid rivastigmine, 479.7g microcrystalline cellulose (microcrystalline cellulose 12
(Vivapur12)), 157.5g METHOCEL K100MCR (methylcellulose K100M (Methocel K100M)),
After 5.4g aluminium-magnesium silicate (Cab-O-Sil) and 10.5g magnesium stearate are mixed, in roll squeezer (roller
Compactor granulation is compressed in), so as to prepare the dry type particulate matter of sustained release phase.
382.5g in obtained pH- dependences sustained release phase particulate matter (is contained into 43.2g tartaric acid rivastigmines
It is bright) and 667.5g (containing 14.4g tartaric acid rivastigmine) sustained release phase dry type particulate matter mixed after, rotary
It is compressed in tablet press machine (Rotary Tablet Press) so that tablet is made, and makes every sheet weight be 350mg.Contain in every
There is 19.2mg tartaric acid rivastigmine, and make to contain 14.4mg in pH- dependence sustained release phases, be sustained in phase and contain
4.8mg tartaric acid rivastigmine.
Embodiment 6
After 500g blank pill (Non-Pareil (300~425 μm)) is fluidized in fluidized-bed coating machine, by 96g's
Tartaric acid rivastigmine and 10g hydroxypropyl methyl cellulose (Methocel E5) and 34g talcum powder be added to ethanol and
The in the mixed solvent of purified water prepares coating liquid, and is sprayed with bottom spray regime, and medicine layer is formed so as to coat.Make shape
Into spheric granules Logistics after, spray and 20g Opadry (Opadry) 03K19229 be dissolved into the mixed of ethanol and purified water
Coating liquid in bonding solvent, after increasing time coat, spray 800g aqueous ethylcellulose dispersion liquid (Surelease)
The coating liquid that is distributed in purified water and increase slow release layer, so as to which sustained release phase piller be made.The piller prepared according to the method described above,
For standard weights 102mg, the tartaric acid rivastigmine containing 9.6mg.Then, to above-mentioned sustained release phase piller, fluidisation is utilized
Bed seed-coating machine sprays prepared by being preferably distributed to refined gram of 400g in purified water coating liquid with bottom spray regime, so as to increase
Add pH- dependence coats, described refined gram is that Eudragit L100-55 is formed preferably by pH- dependent polymers.According to the method described above
The pH- dependence sustained release phase pillers of preparation, for standard weights 142mg, the tartaric acid rivastigmine containing 9.6mg.
After 153g sustained release phase piller is mutually mixed with 639g pH- dependence sustained releases, hard rubber is added to
In capsule so that contain 264mg in each capsule.Tartaric acid rivastigmine containing 19.2mg in each capsule, wherein, pH-
Rivastigmine containing 14.4mg in dependence sustained release phase, it is sustained the rivastigmine containing 4.8mg in phase.
Comparative example 1
By 19.2g tartaric acid rivastigmine, 271.3g microcrystalline cellulose (microcrystalline cellulose 12
(Vivapur12)), 56g METHOCEL K100MCR (methylcellulose K100M (Methocel K100M)) and 3.5g
Magnesium stearate mixed after, be compressed and tablet be made.Tartaric acid rivastigmine containing 19.2mg in every.
Comparative example 2
After 400g initiator core 100 (180~250 μm) is fluidized in fluidized-bed coating machine, by 192g tartaric acid
Rivastigmine and 20g hydroxypropyl methyl cellulose (Methocel E5) and 148g talcum powder are added to ethanol and purification
The in the mixed solvent of water prepares coating liquid, and is sprayed with bottom spray regime, and medicine layer is formed so as to coat.Make what is formed
After spheric granules Logistics, spray 40g Opadry (Opadry) 03K19229 is dissolved into ethanol and purified water mixing it is molten
Coating liquid in agent, after increasing time coat, sprayed 1,600g aqueous ethylcellulose dispersion liquid thereon
(Surelease) prepared by being distributed to together with 200g talcum powder in purified water coating liquid, relied on so as to prepare without pH-
The high molecular sustained release phase of property.The particulate matter prepared according to the method described above, for standard weights 70mg, the tartaric acid containing 9.6mg
Rivastigmine.
In addition, by 4.8g tartaric acid rivastigmine, 182.4g microcrystalline cellulose (microcrystalline cellulose 12
(Vivapur12)), 52.5g METHOCEL K100MCR (methylcellulose K100M (Methocel K100M)),
After 1.8g aluminium-magnesium silicate (Cab-O-Sil) and 3.5g magnesium stearate are mixed, granulation is compressed in roll squeezer, from
And prepare the dry type particulate matter of sustained release phase.
By it is obtained sustained release phase fluid bed granulate thing in 105.0g (containing 14.4g tartaric acid rivastigmine) and
After the dry type particulate matter of 245.0g (containing 4.8g tartaric acid rivastigmine) sustained release phase is mixed, it is compressed to be made
Tablet, and make every sheet weight be 350mg.Tartaric acid rivastigmine containing 19.2mg in every.
Experimental example 1
Tablet in above-described embodiment and comparative example is respectively taken it is a piece of, and in 37 DEG C, 750mL 0.1N HCl dissolution fluids
In, carry out dissolution experiment using slurry (paddle) method and with 50rpm rotating condition.Dissolution experiment start after after 2 hours,
The 250mL alkali phosphates of 0.25M tri- are added, so as to change pH.In each acquisition time, 5mL is taken respectively and utilizes molecular filter
After being filtered, analyzed using liquid chromatography (Liquid chromatographic method).
Table 2
Experimental example 2
Above-described embodiment 1, the tablet of embodiment 3 and comparative example 1 and commercially available exelon capsule (Exelon Cap.) is right
Beasle dog is administered, and analysis experiment has been carried out to blood concentration.The beasle dog for being used in experiment is opened from the previous day of administration
Begin jejunitas, after empty stomach, after it is taken in usually 1/3 amount of food in the morning, to 6 beasle dogs and 30ml water in every group
Embodiment 1 and 1/2 (the tartaric acid rivastigmine 9.6mg) and exelon capsule of embodiment 3 and comparative example 1 are applied together
(tartaric acid rivastigmine 4.8mg).Blood is gathered from the brachial vein of beasle dog, and puts it into test tube of hepari culture tube
In (heparinized culture tube), (3000rpm, 10 minutes) is then centrifuged so as to isolate blood plasma,
And utilize the concentration of rivastigmine in Liquid Chromatography-Tandem Mass Spectrometry (LC/MS/MS) measure blood.
Table 3
The result of experiment, tartaric acid rivastigmine content is taken and has divided for 9.6mg embodiment 1 and the AUC of embodiment 3
Yue Wei be in the case of exelon capsule (tartaric acid rivastigmine 4.8mg) 2.5 times and 2.3 times, ensure that sufficiently
Bioavailability, moreover, compared to exelon capsule, show equal or more low value highest blood concentration (Cmax)。
On the other hand, it has been confirmed that the AUC for not containing the comparative example 1 of pH- dependence particles is shown as 2 times of exelon capsule or so,
But highest blood concentration (Cmax) 1.9 times or so are shown as, fail to be controlled burst size at initial stage.
Claims (9)
1. a kind of slow release medical composition containing rivastigmine, it is characterised in that take for 1st once and relied on containing pH-
Property sustained release phase.
2. the slow release medical composition according to claim 1 containing rivastigmine, it is characterised in that the pH- according to
Rely the property sustained release mutually macromolecule containing the property with dissolving in more than pH5.0, and it is described containing rivastigmine
Slow release medical composition is prepared to particle, ball, core tablet form.
3. the slow release medical composition according to claim 1 or 2 containing rivastigmine, it is characterised in that only exist
The macromolecule of the property with dissolving is selected from acrylic copolymer, hydroxypropyl methyl cellulose neighbour's benzene during more than pH5.0
One or more of dicarboxylic acid esters, cellulose acetate phthalate and their mixture.
4. the slow release medical composition according to claim 1 or 2 containing rivastigmine, it is characterised in that the pH-
The rivastigmine that dependence sustained release mutually contains accounts for 25~90 weight % scopes of total rivastigmine content.
5. the slow release medical composition according to claim 1 or 2 containing rivastigmine, it is characterised in that described
On the basis of pH- dependence sustained release phases, further containing pH- dependent/non-dependent sustained-release matrixes.
6. the slow release medical composition according to claim 1 containing rivastigmine, it is characterised in that non-containing pH-
Dependence is sustained phase, and pH- dependent/non-dependents sustained release is in mutually with pH- dependences sustained release in the form of mutually integral or the shape that separates
State.
7. the slow release medical composition according to claim 6 containing rivastigmine, it is characterised in that with matrix,
Grain, the form of ball contain pH- dependent/non-dependents sustained release phase.
8. the slow release medical composition according to claim 6 containing rivastigmine, it is characterised in that the pH- is non-
The rivastigmine that dependence sustained release mutually contains accounts for 10~75 weight % scopes of total rivastigmine content.
9. the slow release medical composition according to claim 1 containing rivastigmine, it is characterised in that described medical group
The rivastigmine of compound dissolution be within 120 minutes initial stages of dissolution total rivastigmine content 10 weight % less than
40 weight %, in 6 hours for 40 weight % less than 70 weight %, in 12 hours it was more than 70 weight %.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2015-0058759 | 2015-04-27 | ||
| KR1020150058759A KR101990951B1 (en) | 2015-04-27 | 2015-04-27 | A sustained releasing Pharmaceutical Composition comprising Rivastigmine |
| PCT/KR2016/004380 WO2016175546A2 (en) | 2015-04-27 | 2016-04-27 | Rivastigmine-containing sustained-release pharmaceutical composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107530290A true CN107530290A (en) | 2018-01-02 |
| CN107530290B CN107530290B (en) | 2021-04-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201680024737.4A Active CN107530290B (en) | 2015-04-27 | 2016-04-27 | Sustained-release pharmaceutical composition containing rivastigmine |
Country Status (21)
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| US (1) | US10835497B2 (en) |
| EP (1) | EP3290023B1 (en) |
| JP (1) | JP6787928B2 (en) |
| KR (1) | KR101990951B1 (en) |
| CN (1) | CN107530290B (en) |
| AU (1) | AU2016255302B2 (en) |
| BR (1) | BR112017022478B1 (en) |
| CA (1) | CA2984235C (en) |
| CY (1) | CY1124339T1 (en) |
| DK (1) | DK3290023T3 (en) |
| ES (1) | ES2860694T3 (en) |
| HR (1) | HRP20210434T1 (en) |
| HU (1) | HUE053816T2 (en) |
| LT (1) | LT3290023T (en) |
| MX (1) | MX2017013481A (en) |
| PL (1) | PL3290023T3 (en) |
| PT (1) | PT3290023T (en) |
| RS (1) | RS61548B1 (en) |
| RU (1) | RU2727721C2 (en) |
| SI (1) | SI3290023T1 (en) |
| WO (1) | WO2016175546A2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR102209420B1 (en) * | 2019-03-08 | 2021-01-29 | 에이치엘비제약 주식회사 | Oral tablet composition for constant(zero-order) and sustained release of Rivastigmine |
| CN112546037A (en) * | 2020-12-08 | 2021-03-26 | 苏州大学 | Application of rivastigmine in preparation of anti-radiation medicine |
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2016
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- 2016-04-27 SI SI201631161T patent/SI3290023T1/en unknown
- 2016-04-27 US US15/569,693 patent/US10835497B2/en active Active
- 2016-04-27 RU RU2017136567A patent/RU2727721C2/en active
- 2016-04-27 DK DK16786732.4T patent/DK3290023T3/en active
- 2016-04-27 JP JP2017555575A patent/JP6787928B2/en active Active
- 2016-04-27 PL PL16786732T patent/PL3290023T3/en unknown
- 2016-04-27 CN CN201680024737.4A patent/CN107530290B/en active Active
- 2016-04-27 HU HUE16786732A patent/HUE053816T2/en unknown
- 2016-04-27 EP EP16786732.4A patent/EP3290023B1/en active Active
- 2016-04-27 RS RS20210290A patent/RS61548B1/en unknown
- 2016-04-27 BR BR112017022478-0A patent/BR112017022478B1/en active IP Right Grant
- 2016-04-27 MX MX2017013481A patent/MX2017013481A/en unknown
- 2016-04-27 AU AU2016255302A patent/AU2016255302B2/en active Active
- 2016-04-27 CA CA2984235A patent/CA2984235C/en active Active
- 2016-04-27 LT LTEP16786732.4T patent/LT3290023T/en unknown
- 2016-04-27 ES ES16786732T patent/ES2860694T3/en active Active
- 2016-04-27 WO PCT/KR2016/004380 patent/WO2016175546A2/en active Application Filing
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- 2021-04-14 CY CY20211100324T patent/CY1124339T1/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| JP2018514530A (en) | 2018-06-07 |
| US20180125785A1 (en) | 2018-05-10 |
| WO2016175546A2 (en) | 2016-11-03 |
| CA2984235C (en) | 2023-02-21 |
| PL3290023T3 (en) | 2021-08-30 |
| AU2016255302A1 (en) | 2017-12-07 |
| MX2017013481A (en) | 2018-05-17 |
| RU2017136567A (en) | 2019-05-27 |
| CA2984235A1 (en) | 2016-11-03 |
| BR112017022478A2 (en) | 2018-07-10 |
| DK3290023T3 (en) | 2021-04-12 |
| SI3290023T1 (en) | 2021-08-31 |
| JP6787928B2 (en) | 2020-11-18 |
| AU2016255302B2 (en) | 2021-03-04 |
| EP3290023A2 (en) | 2018-03-07 |
| EP3290023B1 (en) | 2021-02-17 |
| PT3290023T (en) | 2021-03-24 |
| RU2727721C2 (en) | 2020-07-23 |
| WO2016175546A3 (en) | 2016-12-22 |
| ES2860694T3 (en) | 2021-10-05 |
| EP3290023A4 (en) | 2018-12-19 |
| BR112017022478B1 (en) | 2023-11-21 |
| HRP20210434T1 (en) | 2021-04-30 |
| US10835497B2 (en) | 2020-11-17 |
| KR20160127405A (en) | 2016-11-04 |
| CN107530290B (en) | 2021-04-27 |
| RS61548B1 (en) | 2021-04-29 |
| HUE053816T2 (en) | 2021-07-28 |
| CY1124339T1 (en) | 2022-07-22 |
| LT3290023T (en) | 2021-03-25 |
| RU2017136567A3 (en) | 2019-09-19 |
| KR101990951B1 (en) | 2019-06-20 |
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